Curcumin, a naturally occurring dietary polyphenol, has shown significant potential as a chemopreventive in cell culture models of breast cancer. However, curcumin suffers from poor oral bioavailability in vivo, resulting in sub-optimal systemic exposure following oral administration. The inability to achieve effective plasma and tissue concentrations following oral administration is a critical problem, because this limits curcumin's potential as a chemopreventive in breast cancer. The long-term objective of this research is to develop a once-a-year depot formulation of dietary polyphenols like curcumin that could significantly lower the risk of developing breast cancer, especially in women at high risk of developing breast cancer (specific gene mutations, Her-2 amplification, etc). The objective of this R03 grant application is to develop advanced preliminary data regarding the chemopreventive efficacy of a polymeric sustained release curcumin formulation in a transgenic model of ErbB2-driven breast cancer. Our limited preliminary studies show that microspheres formulated from the biodegradable poly(D,L-lactide-co-glycolide) polymer can efficiently encapsulate curcumin and sustain its release in mouse over several weeks. The central hypothesis of this research is that increased and prolonged systemic availability of curcumin following subcutaneous administration of a sustained release microsphere formulation will result in effective chemoprevention. To test this hypothesis, two Specific Aims will be addressed. In Specific Aim 1, we will develop a microsphere formulation that releases curcumin over a 3-month period and determine the systemic exposure of curcumin following a single subcutaneous dose of the formulation. In addition, pharmacodynamics of curcumin will be determined by evaluating several chemoprevention biomarkers. In Specific Aim 2, we will investigate the chemopreventive efficacy of sustained release microspheres in the BALB-neuT model of breast cancer. ErbB2 expression, pre-malignant inflammation response in the mammary epithelium, and tumor multiplicity will be used as endpoints to establish the chemopreventive efficacy of curcumin microspheres. Collectively, these studies will help us in acquiring critical preliminary data regarding the chemopreventive efficacy of sustained release curcumin microspheres. If the proposed approach is successful, results of this research will suggest a novel chemoprevention modality for breast cancer.